Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease

The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer’s disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota–gut–brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD.

Download Full-text

Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205015666180904155908 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1179-1190 ◽

Cited By ~ 21

Author(s):

Vilma M. Junges ◽

Vera E. Closs ◽

Guilherme M. Nogueira ◽

Maria G.V. Gottlieb

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Central Nervous System ◽

Nervous System ◽

Gut Microbiota ◽

System A ◽

Bidirectional Communication ◽

The Central Nervous System ◽

The Brain

The role of diet and gut microbiota in the pathophysiology of neurodegenerative diseases, such as Alzheimer's, has recently come under intense investigation. Studies suggest that human gut microbiota may contribute to the modulation of several neurochemical and neurometabolic pathways, through complex systems that interact and interconnect with the central nervous system. The brain and intestine form a bidirectional communication axis, or vice versa, they form an axis through bi-directional communication between endocrine and complex immune systems, involving neurotransmitters and hormones. Above all, studies suggest that dysbiotic and poorly diversified microbiota may interfere with the synthesis and secretion of neurotrophic factors, such as brain-derived neurotrophic factor, gammaaminobutyric acid and N-methyl D-Aspartate receptors, widely associated with cognitive decline and dementia. In this context, the present article provides a review of the literature on the role of the gutbrain axis in Alzheimer's disease.

Download Full-text

Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

Molecular Neurobiology ◽

10.1007/s12035-020-02073-3 ◽

2020 ◽

Vol 57 (12) ◽

pp. 5026-5043 ◽

Cited By ~ 2

Author(s):

Shan Liu ◽

Jiguo Gao ◽

Mingqin Zhu ◽

Kangding Liu ◽

Hong-Liang Zhang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Gut Dysbiosis ◽

Bidirectional Communication ◽

Significant Research ◽

Novel Therapeutic Strategies ◽

The Brain ◽

Brain Homeostasis ◽

Gut Microbiota Composition

Abstract Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

Download Full-text

Gut Microbiota and Alzheimer’s Disease: Experimental Evidence and Clinical Reality

Current Alzheimer Research ◽

10.2174/1567205018666210907160854 ◽

2021 ◽

Vol 18 ◽

Author(s):

Sarama Saha ◽

Sukhpal Singh ◽

Suvarna Prasad ◽

Amit Mittal ◽

Anil Kumar Sharma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Experimental Evidence ◽

Molecular Mechanisms ◽

Bacterial Flora ◽

Experimental Studies ◽

The Elderly ◽

The Impact ◽

The Brain

: Alzheimer’s disease (AD) is characterized by progressive death of neuronal cells in the regions of the brain concerned with memory and cognition, and is the major cause of dementia in the elderly population. Various molecular mechanisms, metabolic risk factors and environmental triggers contributing to the genesis and progression of AD are under intense investigations. The present review has dealt with the impact of a highly discussed topic of gut microbiota affecting the neurodegeneration in the AD brain. A detailed description of the composition of gut bacterial flora and its interaction with the host has been presented, followed by an analysis of key concepts of bi- directional communication between gut microbiota and the brain. The substantial experimental evidence of gut microbiota affecting the neurodegenerative process in experimental AD models has been described next in this review, and finally, the limitations of such experimental studies vis-a- vis the actual disease and the paucity of clinical data on this topic have also been mentioned.

Download Full-text

Biomarkers for Microglial Activation in Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/939426 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Ronald Lautner ◽

Niklas Mattsson ◽

Michael Schöll ◽

Kristin Augutis ◽

Kaj Blennow ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Inflammatory Responses ◽

Innate Immune ◽

First Line ◽

The Central Nervous System ◽

Underlying Mechanisms ◽

The Brain ◽

Neuroimaging Techniques

Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.

Download Full-text

A Large-scale Comparison of Cortical and Subcortical Structural Segmentation Methods in Alzheimer’s Disease: a Statistical Approach

10.1101/2020.08.18.256321 ◽

2020 ◽

Author(s):

Jafar Zamani ◽

Ali Sadr ◽

Amir-Homayoun Javadi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Automated Segmentation ◽

Resonance Imaging ◽

Brain Areas ◽

Segmentation Methods ◽

Magnetic Resonance Imaging Mri ◽

Underlying Mechanisms ◽

The Brain

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that leads to anatomical atrophy, as evidenced by magnetic resonance imaging (MRI). Automated segmentation methods are developed to help with the segmentation of different brain areas. However, their reliability has yet to be fully investigated. To have a more comprehensive understanding of the distribution of changes in AD, as well as investigating the reliability of different segmentation methods, in this study we compared volumes of cortical and subcortical brain segments, using automated segmentation methods in more than 60 areas between AD and healthy controls (HC).MethodsA total of 44 MRI images (22 AD and 22 HC, 50% females) were taken from the minimal interval resonance imaging in Alzheimer’s disease (MIRIAD) dataset. HIPS, volBrain, CAT and BrainSuite segmentation methods were used for the subfields of hippocampus, and the rest of the brain.ResultsWhile HIPS, volBrain and CAT showed strong conformity with the past literature, BrainSuite misclassified several brain areas. Additionally, the volume of the brain areas that successfully discriminated between AD and HC showed a correlation with mini mental state examination (MMSE) scores. The two methods of volBrain and CAT showed a very strong correlation. These two methods, however, did not correlate with BrainSuite.ConclusionOur results showed that automated segmentation methods HIPS, volBrain and CAT can be used in the classification of AD and HC. This is an indication that such methods can be used to inform researchers and clinicians of underlying mechanisms and progression of AD.

Download Full-text

Relationship between Wine Consumption, Diet and Microbiome Modulation in Alzheimer’s Disease

Nutrients ◽

10.3390/nu12103082 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3082

Author(s):

M. Victoria Moreno-Arribas ◽

Begoña Bartolomé ◽

José L. Peñalvo ◽

Patricia Pérez-Matute ◽

Maria José Motilva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Intestinal Microbiome ◽

Dietary Polyphenols ◽

Age Related ◽

Wine Polyphenols ◽

The Impact

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to the most common form of dementia in elderly people. Modifiable dietary and lifestyle factors could either accelerate or ameliorate the aging process and the risk of developing AD and other age-related morbidities. Emerging evidence also reports a potential link between oral and gut microbiota alterations and AD. Dietary polyphenols, in particular wine polyphenols, are a major diver of oral and gut microbiota composition and function. Consequently, wine polyphenols health effects, mediated as a function of the individual’s oral and gut microbiome are considered one of the recent greatest challenges in the field of neurodegenerative diseases as a promising strategy to prevent or slow down AD progression. This review highlights current knowledge on the link of oral and intestinal microbiome and the interaction between wine polyphenols and microbiota in the context of AD. Furthermore, the extent to which mechanisms bacteria and polyphenols and its microbial metabolites exert their action on communication pathways between the brain and the microbiota, as well as the impact of the molecular mediators to these interactions on AD patients, are described.

Download Full-text

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽

10.1136/gutjnl-2018-317431 ◽

2019 ◽

Vol 69 (2) ◽

pp. 283-294 ◽

Cited By ~ 32

Author(s):

Min-Soo Kim ◽

Yoonhee Kim ◽

Hyunjung Choi ◽

Woojin Kim ◽

Sumyung Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurofibrillary Tangles ◽

Immune Cell ◽

Amyloid Β ◽

Memory Deficits ◽

Faecal Microbiota ◽

Inflammatory Monocytes ◽

The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Download Full-text

Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph12020093 ◽

2019 ◽

Vol 12 (2) ◽

pp. 93 ◽

Cited By ~ 12

Author(s):

Shashank Masaldan ◽

Abdel Ali Belaidi ◽

Scott Ayton ◽

Ashley I. Bush

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hydroxyl Radicals ◽

Iron Accumulation ◽

Brain Iron ◽

Dependent Cell ◽

Cellular Dysfunction ◽

The Impact ◽

The Brain

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

Download Full-text

Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model

Scientific Reports ◽

10.1038/s41598-020-71767-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Juan Jose Fernandez-Valenzuela ◽

Raquel Sanchez-Varo ◽

Clara Muñoz-Castro ◽

Vanessa De Castro ◽

Elisabeth Sanchez-Mejias ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuroprotective Effect ◽

Disease Model ◽

Stabilizing Agents ◽

Microtubule Stabilization ◽

Cognitive Improvement ◽

Epothilone D ◽

The Impact ◽

The Brain

Abstract In Alzheimer’s disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology.

Download Full-text

Impact of Tau on Neurovascular Pathology in Alzheimer's Disease

Frontiers in Neurology ◽

10.3389/fneur.2020.573324 ◽

2021 ◽

Vol 11 ◽

Author(s):

Elisa Canepa ◽

Silvia Fossati

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Neurovascular Unit ◽

Amyloid Angiopathy ◽

Brain Vasculature ◽

Mitochondrial Alterations ◽

Species Production ◽

The Impact ◽

The Brain

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.

Download Full-text